The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner Journal Article
| Authors: | Joseph, E. W.; Pratilas, C. A.; Poulikakos, P. I.; Tadi, M.; Wang, W.; Taylor, B. S.; Halilovic, E.; Persaud, Y.; Xing, F.; Viale, A.; Tsai, J.; Chapman, P. B.; Bollag, G.; Solit, D. B.; Rosen, N. |
| Article Title: | The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner |
| Abstract: | Tumors with mutant BRAF and some with mutant RAS are dependent upon ERK signaling for proliferation, and their growth is suppressed by MAPK/ERK kinase (MEK) inhibitors. In contrast, tumor cells with human EGF receptor (HER) kinase activation proliferate in a MEK-independent manner. These findings have led to the development of RAF and MEK inhibitors as anticancer agents. Like MEK inhibitors, the RAF inhibitor PLX4032 inhibits the proliferation of BRAF V600E tumor cells but not that of HER kinase-dependent tumors. However, tumors with RAS mutation that are sensitive to MEK inhibition are insensitive to PLX4032. MEK inhibitors inhibit ERK phosphorylation in all normal and tumor cells, whereas PLX4032 inhibits ERK signaling only in tumor cells expressing BRAFV600E. In contrast, the drug activates MEK and ERK phosphorylation in cells with wildtype BRAF. In BRAFV600E tumor cells, MEK and RAF inhibitors affect the expression of a common set of genes. PLX4032 inhibits ERK signaling output in mutant BRAF cells, whereas it transiently activates the expression of these genes in tumor cells with wild-type RAF. Thus, PLX4032 inhibits ERK signaling output in a mutant BRAF-selective manner. These data explainwhythe drug selectively inhibits the growth of mutant BRAF tumors and suggest that it will not cause toxicity resulting from the inhibition of ERK signaling in normal cells. This selectivity may lead to a broader therapeutic index and help explain the greater antitumor activity observed with this drug than with MEK inhibitors. |
| Keywords: | signal transduction; mitogen activated protein kinase; controlled study; protein expression; protein phosphorylation; gene mutation; human cell; genetics; mutation; raf protein; cell proliferation; metabolism; reverse transcription polymerase chain reaction; apoptosis; gene expression profiling; amino acid substitution; mitogen activated protein kinase inhibitor; epidermal growth factor receptor; antineoplastic activity; enzyme activation; drug effect; cell line, tumor; drug selectivity; phosphorylation; wild type; gene expression regulation; blotting, western; gene expression regulation, neoplastic; drug antagonism; reverse transcriptase polymerase chain reaction; oligonucleotide array sequence analysis; sulfonamide; sulfonamides; tumor cell line; western blotting; tumor cell; drug derivative; extracellular signal-regulated map kinases; ras protein; dna microarray; tumor growth; indoles; tumor gene; indole derivative; b raf kinase; mitogen activated protein kinase kinase; mitogen-activated protein kinase kinases; cell cycle g1 phase; g1 phase; proto-oncogene proteins b-raf; braf protein, human; cell mutant; growth inhibition; plx 4032; n (2,3 dihydroxypropoxy) 3,4 difluoro 2 (2 fluoro 4 iodoanilino)benzamide; benzamide derivative; benzamides; diphenylamine |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 107 |
| Issue: | 33 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2010-08-17 |
| Start Page: | 14903 |
| End Page: | 14908 |
| Language: | English |
| DOI: | 10.1073/pnas.1008990107 |
| PUBMED: | 20668238 |
| PROVIDER: | scopus |
| PMCID: | PMC2930420 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 14" - "Export Date: 20 April 2011" - "CODEN: PNASA" - "Source: Scopus" |
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